All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Strong correlation exists between over expression of glycogen synthase kinase 3 beta (GSK3β) and cancer progression in humans. Activation of GSK3β up-regulates proliferation and increases resistance to apoptosis in cancer cells through activation of pro-survival pathways including the NF-κB pathway. These observations suggest that inhibition of GSK3β is a potential treatment strategy for many cancers. However, while GSK3β inhibitors decrease cancer cell proliferation, they stimulate the conversion of cancer cells to ones that are more likely to invade surrounding normal tissue and metastasize. This conversion to an invasive metastatic state is called epithelial mesenchymal transition (EMT). EMT is also associated with cancer cells that are more resistant to therapies because of the cancer cell converting to a cancer stem cell (or stemness).
This invention demonstrates that inhibitors of the enzyme histone deacetylase (HDAC) prevent EMT and enhance the anti-tumor effect of inhibitors of GSK3β, and provides compounds, compositions, methods and kits for treating various conditions including but not limited to cancers and tumors.